Antiphlogistic 1-(hydroxy or carboxylic acyloxy)-3-(2{40 -halo-4-biphenylyl)

ABSTRACT

Compounds of the formula   WHEREIN R1 is hydrogen or halo, R2 is hydrogen or lower alkyl of 1 to 3 carbon atoms and R3 is hydrogen or organic acyl, with the proviso that R1 and R2 are not hydrogen at the same time, if R3 is hydrogen or acetyl, or OPTICALLY ACTIVE ANTIPODES THEREOF; THE COMPOUNDS AS WELL AS THEIR OPTICALLY ACTIVE ANTIPODES ARE USEFUL AS ANTIPHLOGISTICS WITH A SURPRISINGLY SMALL ULCEROGENIC SIDE EFFECT.

United States Patent [191 Nick] et al.

[4 1 Nov. 18,1975

[ ANTIPHLOGISTIC l-(HYDROXY OR CARBOXYLIC ACYLOXY)-3-(2 '-HALO-4-BIPHENYLYL) [75] Inventors: Josef Nick]; Helmut Teufel;

Wolfhard Engel; Ernst Seeger; Gunther Engelhardt, all of Biberach an der Riss, Germany [73] Assignee: Boehringer Ingelheim GmbH,

Ingelheim am-Rhein, Germany [22] Filed: May 29, 1974 [21] App]. No.: 474,181

[30] Foreign Application Priority Data June 7. 1973 Germany 2328973 [52] US. Cl 260/295 R; 260/295.5 R; 260/468;

[51] Int. Cl. C07D 213/30; A61K 31/44 [58] Field of Search 260/295 R, 295.5 R

[56] References Cited OTHER PUBLICATIONS Hoppe-Seylers Zeitschrift fur Physiologische Chemie 290, 61-63 (1952).

Logemann, Chemical Abstracts 49:1751h (1955). Chemical Abstracts 53:9189h (1959).

Primary Examiner-Norman A. Drezin Attorney, Agent, or Firm-Hammond & Littell [57] ABSTRACT Compounds of the formula wherein R is hydrogen or halo,

R is hydrogen or lower alkyl of l to 3 carbon atoms and R is hydrogen or organic acyl, with the proviso that R and R are not hydrogen at the same time, if R is hydrogen or acetyl, or optically active antipodes thereof; the compounds as well as their optically active antipodes are useful as antiphlogistics with a surprisingly small ulcerogenic side effect.

i 2 Claims, No Drawings C-CH wherein R is hydrogen or halo,

R is hydrogen or lower alkyl of l to 3 carbon atoms and R is hydrogen or organic acyl; with theproviso that R and R are not hydrogen at the same time, if f R is hydrogen or acetyl, or

optically active antipodes thereof.

A particularly preferred subgenus of the compounds according to the invention are those compounds of the formula H 0 1 II C- -CH Y C v 2 0 R3 R wherein R, is hydrogen or halo,

R is hydrogen or lower alkyl of 1 to 3 carbon atoms and R is hydrogen, acetyl, propionyl, butyryl, isobutyryl,

pivaloyl, valeroyl, isovaleroyl, caprinoyl, caproyl,v

Method A By hydrolyzing an enol ether of the formula v 2 /O I R and R have the same meanings as defined above and R is alkyl, aryl or aralkyl in the presence of an acid.

The hydrolysis is' effected in the presence of an acid, preferably in thepresence of a mineral acid such as hydrochloric acid or phosphoric acid, appropriately in a solvent which can be mixed with water, for example, methanol, ethanol, tetrahydrofuran or dioxane, and at temperatures up to the boiling point of the solvent used, preferably, however, at temperatures from 20 to C. A compound of the formula II is conveniently used as cis, trans-mixture.

Method B By decomposing a diazomethyl-ketone of the formula (III) wherein R and R have the same meanings as defined above in the presence of an acid.

The reaction is conveniently performed in the presence of a solvent which can be mixed with water, such as tetrahydrofuran or dioxane, and at temperatures up to the boiling point of the solvent used, preferably, however, at temperatures from 50 to 100C, in the presence of an acid.

If the reaction is performed in the presence of a mineral acid such as sulfuric acid or phosphoric acid, a

compound of formula I is obtained, wherein R is hydrogen.

If the reaction is carried out in the presence of an organic acid of the formula wherein R, has the same meanings as R as defined above except that R;, cannot be hydrogen, optionally in the presence of a catalyst, such as copper (II) chloride, whereby the used organic'acid of formula IV or also an inert solvent such as benzene may serve as solvent, a corresponding compound of formula I is obwherein tained, wherein R; has the same meanings as defined above, except that R;, cannot be hydrogen.

If according to Method A or Method B a compound of formula I is obtained, wherein R is acyl, this acyl may be split off, if desired, by means of hydrolysis, and- /or a compound of formula I, wherein R is hydrogen, this compound may be converted into the corresponding acyl derivative of formula I by means of subsequent acylation; for example, with the corresponding acid halide, acid anhydride or with the corresponding acid in the presence of a chloroformic acid ester, preferably in the presence of an acid binding agent, such as triethylamine or pyridine.

The compounds of formulas II and III used as starting materials are obtained according to known processes. 1

3 base (see Liebigs, Ann. Chem. 699, p. 53 (1966)), and by subsequent reduction of the obtained ester with lithium aluminum hydride. v

The diazomethyl-ketones of formula III are obtained by reaction of the .corresponding biphenylyl-acetyl halides with diazomethane.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

The thin-layer chromatograms were carried out'on preprepared silica gel plates Polygram SlL G/UV of Macherey, Nagel & Co., if not otherwise stated. Preparation of starting compounds:

EXAMPLE 1 Ethyl cis, trans-2-ethoxy-3-( 2 -fluoro-4 -biphenylyl )-butenate- 2 18.6 gm (0.165 mol) of potassium tert.-butylate, suspended in 150 ml of glycol dimethylether, were mixed while stirring with 44.2 gm (0.165 mol) of ethyl 2-diethylphosphono-2-ethoxy-acetate and, after the carbanion had formed, 32.1 gm (0.15 mol) of 2'-fluoro-4- acetyl-biphenyl were added, whereby the mixture heated itself up to 50C while darkening. Then, the mixture was heated up to 80C for 2 hours. After standing overnight, the solvent was removed in vacuo. The residue was mixed with water, the mixture was acidified and extracted with ether. The ether extract ,was washed, dried and evaporated. The oil was distilled for further purification, the yield was 37.1 gm, and the boiling point at 0.6 mm Hg was l70-173C. R value: 0.7 (ethylenechloride/ethyl acetate/glacial acetic acid 100/30/5),

R value: 0.29 and 0.37 (benzene) on Woelm-preprepared silica gel plates F 254/366.

EXAMPLE 2 Cis, trans- 1 -hydroxy-2-ethoxy-3-( 2 -fluoro-4 -biphenylyl)- butene-( 2) 37.1 gm of ethyl cis, trans-2-ethoxy-3-(2-flu0ro-4"- biphenylyl)-butenate-(2), dissolved in 80' ml of dry ether, was added at 60C to 5.2 gm (0.137 mol) of lithium aluminum hydride in 350 ml of absolute ether. Afterwards, the temperature was allowed to rise to C and ml of ethyl acetate, 5.2 ml of water, 5.2 ml of 2N sodium hydroxide' solution and 15.5 ml of water were subsequently added to the reaction mixture. The organic precipitate was vacuum filtered and the ether solution was evaporated to yield 337 gm of oil. R,-value: 0.4 and 0.56 (benzene/ethyl acetate 8/2) on Woelm-preprepared silica gel plates F 254/366.

EXAMPLE 3 Using a procedure analogous to that described in Example 2, cis-trans- 1 -hydroxy-2-ethoxy-3-( 4 biphenylyl)-propene-(2) oil, R value: 0.1 0.2 (benzene), was prepared from ethyl cis, trans-2-ethoxy-3- (4-biphenylyl)-acrylate, m.p. 52 to 59C.

EXAMPLE 4 Using a procedure analogous to thatdescribed in Example 2, cis, trans-1-hydroxy-2-ethoxy-3-(2'-fluoro- 4"-biphenylyl)propene-(2) oil, R value: 0.7 (benzene/ethyl acetate 2/ l was prepared from ethyl cis, trans-2-e'thoxy-3-"(2-fiuoro 4"-biphenylyl)-acrylate oil, R value: 0.4 (benzene/cyclohexane 1:1).

EXAMPLE 5 EXAMPLE 6 Using a procedure analogous to that described in Example 2, cis, trans-1-hydroxy-2-ethoxy-3-(2'-chloro- 4"-biphenylyl)-butene-(2) oil, R value: 0.1 0.2 (benzene), was prepared from ethyl 2-ethoxy-3-(2'-chloro- 4"-biphenylyl)-butenate-(2), b.p. 200-205C at 0.6 mm Hg.

EXAMPLE 7 Using a procedure analogous to that described in Example 2, cis, trans-1-hydroxy-2-ethoxy-3-(4- biphenylyl)-pentene-(2) crystalline solidifying oil, R,- value: 0.2 (benzene), was prepared from ethyl cis, trans-2-ethoxy-3-(4'-biphenylyl)-pentenate-(2), b.p. 1651,80C at 0.6 mm Hg.

Preparation of compounds according to the invention:

EXAMPLE 8 l-Hydroxy-3-( 2 -fluoro -4 -biphenylyl )-butanone-( 2) by Method 'A 32.3 gm of l-hydroxy-2-ethoxy-3-(2-fluoro-4"- biphenylyl)-butene-(2), dissolved in 50 ml of ethanol, were mixed with 4 ml of phosphoric acid and with 25 ml of water and heated for 8 hours at 50C. The reaction product precipitated with water was extracted with ethyl acetate and chromatographically purified on 1200 gm of silica gel (grain size: 0.05 to 0.2 mm; activity stage I) with benzene/ethyl acetate 4/1, after washing, drying and evaporating. After a preliminary run, the fractions having an R -value of 0.6 were collected. 24.6 gm,(84.3% of theory) were obtained as an oil, having 'the formula Elemental Analysis: C H FO (258.3) Calculated: C 74.40%; H 5.85% Found: C 74.50%; H 5.92%

. EXAMPLE 9 Using a procedure analogous to that described in Example 8 l-hydroxy- 3-( 2 -fluoro-4 -biphenylyl propanone-(2) was prepared in a yield of 71% of theory by hydrolysis of l-hydroxy-2-ethoxy-3-(2'-fluoro- 4"-biphenylyl)-propene-(2). The compound was a wax-like substance with an R value of 0.7 (benzene/ethyl acetate 2/1), of the formula 2 c CH2 OH Elemental analysis: C H FO (244.27) Calculated: C 73.76%; H 5.36% Found: C 74.20%; H 5.60%

EXAMPLE Using a procedure analogous to that described in Example 8, 1-hydroxy-3-(4-biphenylyl)-butanone-(2), m.p. 8688C (from cyclohexane), was prepared in a yield of 74% of theory by hydrolysis of l-hydroxy-2- ethoxy-3-(4-biphenylyl)-butene-(2), and had the formula CH2- OH Elemental analysis: C H O (242.32) Calculated: C 79.30%; H 7.49% Found: C 80.20%; H 7.00%

EXAMPLE 1 1 I II ( 3 c CH2 OH Cl Elemental analysis: C H ClO (274.76) Calculated: C 69.94%; H 5.50%; Cl 12.91% Found: C 70.20%; H 5.68%; Cl 12.65%

EXAMPLE 12 Using a procedure analogous to that described in Example 8, l-hydroxy-3-(4'-biphenylyl)-pentanone-(2), m.p. 107-l08C (from cyclohexane), was prepared in a yield of 18% of theory by hydrolysis of l-hydroxy-2- ethoxy-3-(4-biphenylyl)-pentene-(2), and had the formula 6 Elemental analysis: C H O (254.33) Calculated: C 80.28%; H 7.14% Found: C 80.30%; H 7.42%

EXAMPLE l3 1-lsonicotinoyloxy-3-( 2'-fluoro-4"-biphenylyl)-butan one-( 2) 9.1 gm (0.04 mol) of isonicotinic acid anhydride were added to a solution of 8.2 gm (0.0318 mol) ofilhydroxy-3-(2-fluoro-4"-biphenylyl)-butanone-(2) in 50 ml of dry pyridine. The mixture was stirred for a further 2 hours at room temperature under exclusion of moisture; 150 ml of water were added; and the reaction product was extracted with ethyl acetate. The organic layer was washed thoroughly with water to remove the pyridine, dried and evaporated. The residue, a crystalline oil, was recrystallized from 30 ml of isopropanol, m.p. 9597C, in a yield of 7.8 gm (68% of theory), of the formula I II c c CH 0 000 1 2 y CH3 Elemental analysis: C H FNO (363.35) Calculated: C 72.71%; H 4.99%; N 3.86% Found: C 72.90%; H 5.10% N 3.99%

EXAMPLE 14 Using a procedure analogous to that described in Example 13, 1-isonicotinoyloxy-3-(4'-biphenylyl)-butanone-(2), m.p. 89-90C (from ethanol), was prepared in a yield of of theory, from 1-hydroxy-3-(4'- biphenylyl)-butanone-(2) and isonicotinic acid anhydride in pyridine.

EXAMPLE 15 Using a procedure analogous to that described in Example l 3 l-isonicotinoyloXy-3 2 -chl0ro-4 biphenylyl)-butanone-(2), was prepared in a yield of 78% of theory from l-hydroxy-3-(2-chloro-4"biphenylyl)-butanone-(2) and isonicotinic acid anhydride. The compound was purified by column chromatography on silica gel with benzene/ethyl acetate 3/1, andwas an oil with R value: 0.3 (benzene/ethyl acetate 3/1).

Elemental analysis: C H ClNo (379.85) Calculated: C 69.58%; H 4.77%; N 3.69%; Cl 9.33% Found: C 70.30%; H 5.17%; N 3.48%; CI 8.44%

EXAMPLE 16 Using a procedure analogous to that described in Example 13 l-nicotinoyloxy-3- 2 '-fluoro-4 biphenylyl)-butanone-(2), m.p. 89-90C (from isopropanol), was prepared in a yield of 81% of theory, from l-hydroxy-3-( 2 -fluoro-4 '-biphenylyl )-butanone- (2) and nicotinoylchloride hydrochloride in pyridine, and had the formula Elemental analysis: C H FNO (363.35) Calculated: C 72.71%; H 4.99%; N 3.86% Found: ,C 72.70%; H 5.27%; N 3.88%

EXAMPLE 1 7 l-Acetoxy- 3-( 2 -fluoro-4 '-biphenylyl )-butanone-( 2) Elemental analysis: C H FO (300.22) Calculated: C 71.98%; H 5.71% Found: C 72.20%; H 5.76%

EXAMPLE 18 Using a procedure analysis to that described in Example 17, l-pivaloyloxy-3-( 2 '-fluoro-4 -biphenylyl)- butanone-(Z), m.p. 8789C (from isopropanol), was prepared in a yield of 71% of theory, from l-hydroxy-3- (2-fluoro-4"-biphenylyl)-butanone-(2) and pivalic acid chloride, and had the formula I II CH CH Elemental analysis: C H FO (342.39) Calculated: C 73.66%; H 6.77% Found: C 73.90%; H 6.80%

EXAMPLE 19 Using a procedure analogous to that described in Example 17, 1-isobutyry1oxy-3-( 2 -fluoro-4 biphenylyl)-butanone-(2) was prepared in a yield of 90% of theory from 1-hydroxy-3-(2-fluoro-4"- biphenylyl)-butanone-(2) and isobutyric acid chloride. The compound was an oil, R -value: 0.7 (ethylene chloride/ethyl acetate/glacial acetic acid 100/ 30/5 on Woelm-prepared silica gel plates F 254/366), and had the formula H CH 1 ll v 1 0- C-CH 0- CO- CH CH CH 8 Elemental analysis: C H FO (328.39) Calculated: C 73.15%; H 6.45% Found: C 73.50%; H 6.45%

EXAMPLE 20 Using a procedure analogous to that described in Example l 7, 1-va1eryloxy-3-(2'-fluoro-4' '-biphenylyl)- butanone-(2) was prepared in a yield of 86% of theory from 1 -hydroxy-3-( 2 -fl uoro-4 '-biphe nylyl -butanone- (2) and valeric acid chloride. The compound was an oil, R -valuez 0.7 (ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5 on Woelm-preprepared silica gel plates F 254/366), of the formula (E-C-Cll Elemental analysis: C H FO (342.41) Calculated: C 73.26%; H 6.77% Found: C 71.20%; H 6.61%

EXAMPLE 21 Using a procedure analogous to that described in Example 17, l-acetoxy-3-(4'-biphenylyl)-butanone-(2), m.p. 109-1 118C (from methanol), was prepared in a yield of 86% of theory from 1-hydroxy-3(4'- biphenylyl)-butanone-(2) and acetylchloride.

Elemental analysis: c sH gog (282.34) Calculated: C 76.60%; H 6.42% Found: C 76.70%; H 6.50%

EXAMPLE 22 Using a procedure analogous to that described in EX- ample 17, 1-piva1oy1oxy-3-(4-biphenylyl)-butanone- (2), m.p. 77C (from ethanol), was prepared in a yield of 88% of theory, from 1-hydroxy-3-(4- biphenylyl)-butanone-(2) and pivalic acid chloride.

Elemental analysis: C ,H O (324.42) Calculated: C 77.76%; H 7.45% Found: C 77.90%; H 7.52%

EXAMPLE 23 Using a procedure analogous to that described in Example l7, 1-acetoxy-3-(2'-chloro-4"-biphenylyl)-butanone-(2), m.p. 61-62C (from isopropanol), was prepared in a yield of 54% of theory from l-hydroxy-3-(2'- chloro-4"-biphenylyl)-butanone-(2) and acetylchloride.

Elemental analysis: C H ClO (316.79) Calculated: C 68.25%; H 5.41%; C1 11.19% Found: C 68.20%; H 5.44%; Cl 11.11%

EXAMPLE 24 Using a procedure analogous to that described in Example 17, 1-pivaloyloxy-3-(2-chloro-4"-biphenylyl)- butanone-(2) was prepared in a yield of 68% of theory from 1-hydroxy-3-( 2 '-chloro-4' '-bip henylyl )-butanone-(2) and pivalic acid chloride. Purification was by column chromatography on silica gel (activity stage 1, grain size: 0.05 to 0.2 mm) with benzene. The compound was an oil, R,-va1ue: 0.7 (Woelm-preprepared silica gel plates F 254/366; eluens: ethylene chloridelethyl acetate/glacial acetic acid /30/5).

Elemental analysis: C H C1O (358.87) Calculated: C 70.29%; H 6.46%; Cl 9.88% Found: C 70.60%; H 6.44%; C1 9.70%

EXAMPLE 25 Using a procedure analogous to that described in Example 17, 1-(2'-benzofurancarbonyloxy)-3-(2"- fluoro-4"-biphenylyl)-butanone-(2), m.p. 100-102C (from isopropanol), was prepared in a yield of 84% of theory from l-hydroxy-3-( 2 '-fluoro-4 '-biphenylyl)- butanone-(2) and benzofuran-2-carboxylic acid chloride, and having the formula I II Elemental analysis: C H FO (390.41) Calculated: C 73.84%; H 4.90% Found: C 73.80%; H 4.86%

EXAMPLE 26 l-Ben2oyloxy-3-(4-biphenylyl)-proparione-(2) by Method B a. Diazomethyl-4-biphenylylmethyl-ketone 16.8 gm (0.073 mol) of 2-(4'-biphenylyl)-acetylchloride (b.p. of 145C at 0.4 mm Hg), dissolved in 100 ml of dry benzene were added dropwise while stirring at C to 0.16 mol of diazomethane in 360 ml of ether. After all the nitrogen had been formed, the mixture was stirred for a further 5 hours at 0 to 5C, and evapo-v rated after standing overnight. The residue was recrystallized from cyclohexane to yield 15.5 gm (90% of theory) of diazomethyl-4-biphenylylmethyl-ketone, m.p. 9193C. I

b. l-Benzoyloxy-3-( 4 '-biphenylyl )-propanone- 2) 4.7 gm (0.02 mol) of diazomethyl-4-biphenylylmethyl-ketone and 4.9 gm (0.04 mol) of benzoic acid were dissolved in 60 ml of dioxane, 0.4 gm of CuCl were added, the mixture was warmed up to 100C while stirring, whereby nitrogen separated while darkening. The mixture was evaporated in vacuo and the residue was distributed between water and ethyl acetate. The excess of benzoic acid was removed by washing with an aqueous solution of bicarbonate. After drying, evaporating and recrystallization from ethanol, 4.0 gm (61% of theory) were obtained of l-benzoyloxy-3-(4'- biphenylyl)-propanone-(2) of the formula I II c-c -CH2-O-CO m.p. 110-112c. Elemental analysis: C H O (330.38) Calculated: 79.99%; H 5.49% Found: C 80.20%; H 5.72%

EXAMPLE 27 EXAMPLE 28 Using a procedure analogous to that described in Example 17, 1-valeroyloxy-3-(4 '-biphenylyl)-butanone- (2), mp. 54-55C (from methanol), was prepared in a yield of 81% of theory from l-hydroxy-3-(4'- biphenylyl)-butanone-(2) and valeric acid chloride.

Elemental analysis: C H O (324.42) Calculated: C 77.76%; H 7.45% Found: C 77.50%; H 7.48%

EXAMPLE 29 Using a procedure analogous to that described in Example l 7, 1-isovaleroyloxy-3-(4'-biphenylyl)-butanone-( 2), mp. 4143C (from methanol), was prepared in a yield of 82% of theory from 1-hydroxy-3-(4- biphenylyl)-butanone-(2) and isovaleric acid chloride,

Elemental analysis: C H O (342.42) Calculated: C 77.76%; H 7.45% Found: C 77.50%; H 7.46%

EXAMPLE 30 Using a procedure analogous to that described in Example l7, l-caprinoyloxy-3-(4-biphenylyl)-butanone- (2), mp. 4648C (from methanol), was prepared in a yield of 81% of theory from l-hydroxy-3-(4'- biphenylyl)-butanone-(2) and capric acid chloride, and had the formula v u v I 0 H2 0 co 0 11 Elemental analysis: C H O (394.56) Calculated: C

- 79.15%; H 8.68% Found: C 79.20%; H 8.70%

EXAMPLE 3 1 Using a procedure analogous to that described in Example l7, l-propionyloXy 3-(2'-fluoro-4" biphenylyl)- butanone-(2) was prepared from l-hydroxy-3-(2 fluoro-4"-biphenylyl)-butanone-(2) and propionic acid chloride. The purification was carried out by column chromatography on silica gel (activity stage 1, grain size 0.05 to 0.2 mm) with cyclohexane/ethyl/acetate 5/ 1. The yield was 45% of theory of an oil, R,-

1 1 value: 0.70 (Woelm preprepared silica gel plates F 254; eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5).

Elemental analysis: C H FO (314.36) Calculated: C 72.60%; H -6.09% Found: C 72.40%; H 6.32%

EXAMPLE 32 Using a procedure analogous to that described in Example 17, l-butyroyloxy-3-( 2 -fluoro-4 '-biphenylyl)- EXAMPLE 33 Using a procedure analogous to that described in Example l7, l-isovaleroyloxy-3-(2 '-fluoro-4 biphenylyl)-butanone-(2) was prepared from 1- hydroxy-3-( 2 -fluoro-4 -biphenylyl )-butanone-( 2) and isovaleric acid chloride. The purification was carried out by column chromatography on silica gel (activity stage I, grain size: 0.05 to 0.2 mm) with cyclohexane/ethyl acetate 7/ 1. The yield was 41% of theory of an oil with an R value: 0.71 (Woelm preprepared silica gel plates F 254; eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5).

Elemental analysis: C H FO (342.41) Calculated: C 73.66%; H 6.77% Found: C 73.95%; H 7.08%

EXAMPLE 34 I II ('J- C CH -0-CO CH CH Elemental analysis: C H FO (356.44 Calculated: C 74.15%; H 7.07% Found: C 74.30%; H 7.16%

EXAMPLE 35 Using a procedure analogous to that described in Example 17, l-capryloyloxy-3-(2'-fluoro-4"-biphenylyl)- butanone-(2) was prepared from 1-hydroxy-3-(2- 12 fluoro-4"-biphenylyl)-butanone-(2) and caprylic acid chloride. The purification was carried out by column chromatography on silica gel (activity stage 1, grain size: 0.05 to- 0.2 mm) with cyclohexane/ethyl acetate 5 8/1. The yield was 24% of theory of an oil, R value:

0.74 (Woelm preprepared silica gel plates F 254; eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5), having the formula C C C H 0 co C H CH Elemental analysis: C H FO (384.49) Calculated:

C 74.97%; H 7.61% Found: C 75.00%; H 7.57%

EXAMPLE 36 Using a procedure analogous to that described in Ex- 25 ample 1-7, l-caprinoyloxy-3-(2-fluoro-4"-biphenylyl)- butahone-(Z) was prepared from l-hydroxy-3-(2- fluoro-4"-biphenylyl)-butanone-(2) and capric acid chloride. The purification was carried out by column chromatography on silica gel (activity stage 1, grain size: 0.05 to 0.2 mm) with cyclohexane/ethyl acetate 8/1). The yield was 40% of theory of an oil, R value: 0.72 (Woelm preprepared silica gel plates F 254; eluens ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5).

Elemental analysis: C H FO (412.55) Calculated: C 75.70%; H 8.06% Found: C 75.90%; H 8.22%

EXAM PLE 3 7 Using a procedure analogous to that described in Example l 7 1 -undecyloxy- 3-( 2 -fluoro-4 -biphenylyl butanone-(2) was prepared from 1-hydroxy-3-(2'- fluoro-4"-bipheny1y1)-butanone and undecylic acid chloride. The purification was carried out by column chromatography on silica gel (activity state I, grain size: 0.05 to 0.2mm) with cyclohexane/ethyl acetate 8/1). The yield was 46% of theory of an oil, R -value: 0.73 (Woelm preprepared silica gel plates F 254; eluens ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5), having the formula Elemental analysis; 0 M (426.58) Calculated: C 76.03%; H 8.27% Found: C 76.20%; H 8.54%

EXAMPLE 38 1 -1sonicotinoyloxy-3-( 2 -fluoro-4 -bipheny1yl)- bu'tanone-(2) by Method B a. (+)-Diazomethyl-a-( 2 -fluoro-4-biphenylyl)-ethylketone I,

25.4 gm of (+)-2-(2'-fluoro-4"-biphenylyl)-propionic acid ([a],,=+ 53 in methanol) were converted into the oily acid chloride by boiling with thionyl chloride. The acid chloride (31.1 gm 0.118 mol), dissolved in 100 ml of benzene, was added dropwise to a solution of 0.26 mol of diazomethane in 490 ml of ether at a temperature below C. After standing overnight, the mixture was evaporated in vacuo. The remaining oily diazomethyl-a-( 2 '-fluoro-4-biphenylyl )-ethylketone had a R value of 0.6 (Woelm preprepared silica gel plates F 254, eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5).

b. (+)-1-Hydroxy-3-(2-fluoro-4-biphenylyl)-butanone-( 2) 15.8 gm of (+)-diazomethyl-a-(2-fluoro-4- biphenylyl)-ethyl-ketone were dissolved in 240 ml of dioxane; 180 ml of 2N sulfuric acid were added, and the mixture was heated for 1 hour at 40C. After all nitrogen had been formed, the solvent was removed in vacuo, the mixture was extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated in vacuo. The oil obtained had an R value of 0.48 (Woelm preprepared silica gel plates F 254, eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5). The yield was 88% of theory.

0. 1 -Isonicotinoyloxy-3-( 2 'fluoro-4 biphenylyl)-butanone-(2) was prepared using a procedure analogous to that described in Example 17 from 1 -hydroxy-3-( 2 -fluoro-4-bipheny1yl)-butanone- (2) and isonicotinic acid anhydride. The yield was 47% of theory and the compound had a m.p. of 102C and [a] 215 in methanol (C 0.55).

Elemental analysis: C H FNO (363.35) Calculated: C 72.71%; H 4.99%; N 3.86% Found: C 72.50%; H 5.13%; N 3.86%

EXAMPLE 39 1-Acetoxy-3-( 2 -fluoro-4 -biphenylyl )-butanone- (2) by Method B 15.8 gm of (+)-diazomethyl-a-(2'-fluoro-4- biphenylyl)-ethyl-ketone were heated for 1 hour at 100C in 1 ml of glacial acetic acid. After all nitrogen had been formed, the mixture was evaporated in vacuo and the residue was purified by chromatography on 500 gm of silica gel (activity stage 1, grain size: 0.05 to 0.2 mm) with benzene/ethyl acetate 19/ l. The reaction product was recrystallized from methanol, with m.p. 5557C in a yield of 8.1 gm which was 46% of theory, and [04],, 188 (in methanol (C 0.57)).

Elemental analysis: C H FO (300.34) Calculated: C 71.98%; H 5.71% Found: C 71.70%; H 5.71%

EXAMPLE 40 Using a procedure analogous to that described in Example 39 1 -hydroxy-3-( 2 '-fluoro-4 '-biphenylyl butanone-(2) was prepared in a yield of 85% of theory from ()-dia zome thyl-a-( 2 '-fluo ro-4-biphenylyl ethyl-ketone [oil, R,-value: 0.6 (Woelm preprepared silica gel plates F 254; eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5)]. This compound was an oil, R va1ue: 0.50 (Woelm preprepared silica gel plates F 254; eluens: ethylene chloride/ethyl acetate/glacial acetic acid 100/30/5).

EXAMPLE 41 Using a procedure analogous to that described in Example 17, ()-l-isonicotinoyloxy-3-(2'-fluoro-4- biphenylyl)-butanone-(2), m.p. 99-101C, was prepared in a yield of 30% of theory from ()-1-hydroxy- 3-(2'-fluoro 4"-biphenylyl-butanone-(2) and isonicotinic acid anhydride. [011 was 217 in methanol (c 0.47).

Elemental analysis: C22H18FNO3 (363.35) Calculated: C 72.71%; H 4.99%; N 3.86% Found: C 72.70%; H 4.97%; N 3.91%

EXAMPLE 42 Using a procedure analogous to that described in Example 39, ()-1-acetoxy-3-(2-fluoro-4-biphenylyl)- butanone-(Z), m.p. 59-61C, was prepared in a yield of 21% of theory from ()-diazomethyl-a-(2'-fluoro- 4"-biphenylyl)-ethy1-ketone and glacial acetic acid. [04],, was 187 in methanol (c 0.46).

Elemental analysis: C H FO (300.34) Calculated: C 71.98%; H 5.71% Found: C 72.20%; H 5.80%

The pharmacodynamic activities of the compounds of the present invention, namely their antiphlogistic activity with a surprisingly small ulcerogenic side effect, were ascertained in the manner described below. While all of these compounds were found to have these above effective activities, some illustrative test results are shown in the table, wherein A 1-isonicotinoy1oxy-3-(2fluoro-4"-biphenylyl)- butanone-( 2 B l-hydroxy-3-(2-fluoro-4"-biphenylyl)-butanonel-hydroxy-3-( 2 '-fluoro-4 -biphenylyl)-propanone-(2) and D l-valeroyloxy-3-(2-fluoro-4"-biphenylyl)-butanone-(2).

Antiphlogistic activity The antiphlogistic activity was tested to determine the antiexsudative effect on the kaolin-induced edema (see Hillebrecht in Arzneimittelforschung 4, 607 614 (1954)) and the carrageenin-induced edema (see Winter in Proc. Soc. Exper. Biol. Med. 111, 544 1962)) of the hind paw of the rat after oral administration of at least 3 doses to at least 10 animals per dose. The dose leading to a 35% reduction of the swelling (ED was graphically determined.

Ulcerogenic activity:

The ulcerogenic activity in the rat was determined after oral administration of the compound for 3 times after 24 hours each time. The animals were killed 4 hours after that and the number of the animals having an ulcer was calculated. The close which caused an ulcer in 50% of the animals (ED was graphically determined.

Acute toxicity:

The peroral acute toxicity of the compounds was determined on groups of 10 rats each. The LD i.e., the dose administered perorally after which 50% of the animals died within a period of 14 days, was calculated according to the method of Litchfield and Wilcoxon.

The results are shown below in Table I.

TABLE I Substance ED mgm/kg p.o. ED mgm/kg p.o. LDM,

kaolincarrageeninulcer actimgm/kg induced induced vity p.o

edema edema A 14 22.5 71 1.170 B 22.5 22 30 367 c 68 44 70 2.040 D 12.5 12 891 The compounds according to the present invention hydroxy-3-(2'-fluo o-4- or optically active antipodes thereof, embraced by forggg gz'g 28-8 il mula I above, have useful pharmacodynamic proper- Gelatin 3.0 ties. More particularly, the compounds of the present 3 I I I: invention exhibit antiphlogistic activity with surprisdgnes'um stearate T H 33 ingly small ulcerogenic side effects in warm-blooded O a animals, such as rats. For pharmaceut cal purposes the compounds accord- Preparation ing to the present lnventlon are admmlstered to warmblooded animals perorally or parenterally as active in- A mlxtm'e of the actfve ingredient with com Starch gredients in customary dosage unit compositions, that granulated by Passmg through a f is, compositions in dosage unit form consisting essenwltoh an q Q 10% Solutlon ofithe g m, dried at tially of an inert pharmaceutical carrier and one effec- 45 agam passefl throflgh Sald Screen- The g f tive dosage unit of the active ingredient, such as tablets, late Obtamed was mixed Wlth talcum and magneslum Coated pills, Capsules, wafers powders, Solutions, stearate and compressed to form the tablet cores, each pensions, emulsions, syrups, suppositories and the like. having F Welght of 300 gm e tablet cores were One effective single dosage unit of the compounds ac- Coated m known manner Wlth a g P y of cording to the present invention is from 1.67 to 6.67 Sugar and talcum and Pollshed Wlth beeswax- Each mgm/kg body weight, f bl 2 5 to 5 mgm/kg coated tablet welghed 580 mgm and contained 200 b weight mgm of the ketone compound, and was an oral dosage The following examples illustrate a few pharmacemiunit composition with effective antiphlogistic activity. cal dosage un t composmons comprislng a compound EXAMPLE 45 of the present invention as an act1ve 1n gredient and represent the best modes contemplated of putting the in- Gelatm caP511165 Ventlon mto PFaCUCaI The Parts are parts by Welght The capsule contents were compounded from the folunless otherwise specified. lowing ingredients:

1 -hydroxy-3-( 2 -fluoro-4"- EXAMPLE 43 biphenylyl)-propanone(2) 200.0 parts 4() Corn starch 190.0 Tablets Aerosil 6.0 Magnesium stearate 4.0 The tablet composition was compounded from the Total 4 00 m following ingredients:

l-isonicotinoyloxy-3 2 -fluoro- 45 Preparation 4"-bi h 1 l)-b v -(2) 200.0 arts Corn ta r lrh u mom 97.0 P The ingredients were homogeneously mixed and 400 Polyvinyl pyrmlidone mgm portions were filled into size No. 1 gelatin cap- Magnesmm stearate 3.0

Total 310 0 parts sules. Each gelatin capsule contained 200 mgm of the ketone compound and was an oral dosage unit composition with effective antiphlogistic activity.

Preparation: EXAMPLE 4 The mixture of active ingredient with corn starch was suppositories granulated by passlng through a 1.5 mm screen w1th an Th d d f aqueous 14% solution of polyvinylpyrrolidone, dried at SUPPOSIFOYY ff g was Compoun 6 rom 45C and again passed through the said screen. The the Onowmg mgre granulate thus prepared was mixed with magnesium stearate and compressed into 310 mgm tablets. Each 9 b1 t tai d 00 f he k t ne m 0 d 4 -biphcnylyl)-butanone-(2) 100.0 parts ta 6 con m 0 O p 6O Suppos1tory base (e.g. cocoa butter) 1450.0 and was an oral dosage unit composition w1th effective Total 1550.0 parts antiphlogistic activity.

Preparations EXAMPLE-44 The active 1ngred1ent was finely powdered and Coated tablets The tablet core composition was compounded from the following ingredients:

stirred into the molten suppository base at 40C, using an immersion homogenizer. 1550 mgm portions of the mixture at 38C were poured into cooled suppository molds and allowed to cool therein. Each suppository We claim: contained 100 mgm of the ketone compound and was a 1, A und of the formula rectal dosage unit composition with effective antiphlogistic activity. H O

f 5 n Analogous results are obtained when any one of the C CH2 O 3 other compounds embraced by formula I or an optically active antipode thereof is substituted for the par- R, ticular ketone in Example 43 through 46. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert 1 pharmaceutical carrier ingredients may be varied to wher i meet particular requirements. R is hydrogen, fluoro or chloro,

While the present invention has been illustrated with l 5 R is hydrogen or lower alk l f l to 3 carbon atoms the aid of certain specific embodiments thereof, it will, and i be readily apparent to others skilled in the art that the R is nicotinoyl or isonicotinoyl, invention is not limited to these particular embodior an optically active antipode thereof. ments, and that various changes and modifications may 2. A compound according to claim 1, which is 1- be made without departing from the spirit of the invenisonicotinoyloxy-3-(2-fluoro-4"-biphenylyl)-butation or the scope of the appended claims. none-(2), or an optically active antipode thereof. 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1, which is 1-isonicotinoyloxy-3-(2''-fluoro-4''''-biphenylyl)-butanone-(2), or an optically active antipode thereof. 